Close to 1.7 billion people worldwide are asymptomatically infected with Mycobacterium tuberculosis (Mtb), the etiological agent of TB. Co-infection with HIV and the spread of multidrug-resistant (MDR) and extensively drug- resistant (XDR) Mtb strains constitutes a major impediment to worldwide public health control measures. T cell exhaustion, defined as the deterioration of T cell function, is a hallmark of many chronic infections due to prolonged antigen exposure and inflammatory signals present at the site of infection. However, very little is known regarding the link between these functionally exhausted cells and their metabolic insufficiencies, particularly in the context of the human TB/HIV lung. Given that immune activation is critically energy-dependent, and that pathogens cause imbalances in metabolism, there is a gap in our knowledge on how Mtb/HIV reprograms immunometabolic pathways, and whether this can be reversed by host-directed therapy (HDT) to rejuvenate T cell metabolism. Our long-term goal is to understand how Mtb/HIV perturbs host metabolism leading to disease, reactivation, or death of the host, and how this knowledge can be leveraged for therapeutic purposes. Our central hypothesis is that Mtb/HIV dysregulates T cell energy metabolism in the human lung, leading to the suppression of effective immune control of localized infection, which could be restored by HDT. This hypothesis has been formulated based on an unusual global collaborative effort between basic science investigators, cardiothoracic surgeons, and pathologists in South Africa, and epigenetic, proteomic and metabolomic experts in the USA and Europe. Our hypothesis is built upon substantial Preliminary Data which demonstrate the feasibility of routine analyses of freshly resected human TB lung tissue, and show that Mtb controls distinct bioenergetic pathways and immune checkpoints. The rationale is several fold: Firstly, phenotypic characterization of functionally exhausted T cell populations has been largely restricted to animal models, and to date, there have been no studies examining these populations from freshly resected human TB/HIV lung tissue, representing a significant translational gap in our knowledge. Secondly, examining the metabolic requirements of functionally exhausted T cell populations in the human TB/HIV lung will enable us to identify key metabolic checkpoints that may represent novel pharmacological targets for HDT. With greater knowledge of the metabolic checkpoints involved in T cell exhaustion, HDT may be a possible intervention strategy to revitalize these cells and reinvigorate anti-TB immunity. Thirdly, identifying nutritional requirements and metabolic pathways that promote productive T cell responses and hinder the transition towards exhausted T cell programs could provide exciting new benchmarks for TB/HIV vaccine design. The research is innovative, because it represents a new and substantive departure from the status quo by applying novel technologies and unique patient cohorts to examine T cell exhaustion in the human TB lung. This contribution is significant because it has the potential to breach a major barrier in the TB field; routine analysis of freshly resected TB lung tissue.